ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7108A>G (p.Asn2370Asp)

gnomAD frequency: 0.00001  dbSNP: rs767494363
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588629 SCV000293868 uncertain significance not provided 2016-01-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.7108A>G at the cDNA level, p.Asn2370Asp (N2370D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asn2370Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Asn2370Asp occurs at a position that is not conserved and is located within the FAT domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Asn2370Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588629 SCV000694345 uncertain significance not provided 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The ATM c.7108A>G (p.Asn2370Asp) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/120934, which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasia. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp RCV000689779 SCV000817445 uncertain significance Ataxia-telangiectasia syndrome 2023-09-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2370 of the ATM protein (p.Asn2370Asp). This variant is present in population databases (rs767494363, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 246353). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000588629 SCV002010788 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV002365229 SCV002666873 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-05 criteria provided, single submitter clinical testing The p.N2370D variant (also known as c.7108A>G), located in coding exon 48 of the ATM gene, results from an A to G substitution at nucleotide position 7108. The asparagine at codon 2370 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV004567782 SCV005055885 uncertain significance Familial cancer of breast 2024-03-24 criteria provided, single submitter clinical testing

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